Molecular measurements for radiation-induced PTC risk modelling

Transcription

1 Molecular measurements for radiation-induced PTC risk modelling DoReMi 3rd Periodic Meeting Kristian Unger Integrative Biology Group Research Unit of Radiation Cytogenetics Department of Radiation Sciences Helmholtz-Zentrum München

2 Conventional approach Epi-data Risk model PTC risk after exposure to IR How to improve the risk model?

3 EpiRadBio approach Molecular biology measurements Epi-data Risk model PTC risk after exposure to IR Improvement by including measurements on signalling pathways leading to PTC

4 Risk model principles Classic two-stage clonal expansion model

5 Risk model principles Classic two-stage clonal expansion model early changes.

6 Risk model principles Classic two-stage clonal expansion model early changes. Critical lack of knowledge on early changes in PTC development!

7 Early changes in PTC tumourigenesis there are no known pre-lesions in PTC tumourigenesis that would be morphologically detectable Molecular surrogate markers indicating early changes in PTC development?

8 DoReMi 3rd Periodic Meeting Cell proliferation in cancer development cell proliferation is a hallmark in cancer development Hanahan and Weinberg, Cell 2011

9 MAPK pathway Nikiforov, Mod Path (2008) Deregulated MAPK signalling is known to be involved in the majority (> 70%) of PTCs (RET/PTC, BRAF V600E) active MAPK induces cell proliferation, which is a hallmark in cancer development

10 DoReMi 3rd Periodic Meeting MAPK pathway

11 Early changes in PTC tumourigenesis Hypothesis: Active MAPK signalling in differentiated non-malignant thyroid tissue indicates early molecular changes during tumourigenesis.

12 DoReMi 3rd Periodic Meeting Identification of MAPK activation genes in normal tissues 170 genes MAPK pathway* match mrna array probes Abend et al. 145 genes 20 top variant genes hierarchical clustering top 10 informative MAPK activation genes * Wikipathways

13 Identification of MAPK activation genes in normal tissues

14 Identification of MAPK activation genes in normal tissues FOS, DUSP1, DUSP6, JUN, NR4A1, SRF, HSPA1A, GADD45A, MYC

15 DoReMi 3rd Periodic Meeting MAPK pathway ** * * * * * * *

16 Results MAPK activity scoring UkrAm

17 CLIP2 as surrogate for genome instability Hanahan and Weinberg, Cell 2011

18 Reconstructed of CLIP2 network microtubule cytoskeleton organization GTPase activator MAPK inactivation kinesin-family protein-folding, apoptosis RNA splicing protein-folding golgi-apparatus golgi-apparatus

19 CLIP2 as surrogate for genome instability CLIP2 radiation marker in PTC literature knowledge sparse CLIP2 centred interactome analysis 1st neighbours of CLIP2 suggests that CLIP2 is involved in genomic instability, another hallmark of cancer Hanahan and Weinberg, Cell 2011

20 CLIP2 Hypothesis: CLIP2 in PTC tissue represents a surrogate marker of genomic instability in PTC tumourigenesis. Approach: CLIP2 typing according to Selmansberger et al. (Oncogene 2014, in review)

21 Results CLIP2 measurements on UkrAm Tumour tissue CLIP2 marker in PREVALENCE and INCIDENCE of UkrAm % CLIP2_marker negative positive binary (negative/positive) prevalence (n=)22 incidence (n=47)

22 Ongoing activities Measurements of CLIP2 on tumour tissues from belarussian cohort (IntThyr) MAPK activity scoring on normal tissues from belarussian cohort (IntThyr)

23 DoReMi 3rd Periodic Meeting Handing over molecular data to risk modellers